Quinazoline derivatives as egf and/or erbb2 tyrosine kinase inhibitors

Abstract

A quinazoline derivative of the Formula (I): wherein the substituents are as defined in the text for use in the production of an anti proliferative effect which effect is produced alone or in part by inhibiting erbB2 receptor tyrosine kinase in a warm blooded animal such as man.

1 . A quinazoline derivative of Formula I: 
     
       
         
         
             
             
         
       
     
     wherein:
 R 1  is selected from hydrogen, hydroxy, (1-4C)alkoxy and (1-4C)alkoxy(1-4C)alkoxy; 
 G 1 , G 2 , G 3  and G 4  are each, independently, selected from hydrogen and halogeno; 
 X 1  is selected from SO 2 , CO, SO 2 N(R 7 ) and C(R 7 ) 2 , wherein each R 7  is, independently, selected from hydrogen and (1-4C)alkyl; 
 Q 1  is aryl or heteroaryl, which aryl or heteroaryl group optionally bears one or more substituents independently selected from halogeno, cyano and (1-4C)alkoxy; 
 R 2 , R 3 , R 4  and R 5  are each, independently, selected from hydrogen and (1-4C)alkyl, or
 R 2  and R 3  together with the carbon atom to which they are attached form a cyclopropyl ring, or 
 R 4  and R 5  together with the carbon atom to which they are attached form a cyclopropyl ring; 
 
 R 6  is selected from hydrogen and (1-4C)alkyl; 
 A is selected from hydrogen, Z-(CR 8 R 9 ) p — and R 10 ; 
 p is 1, 2, 3, or 4; 
 R 8  and R 9  are each, independently, selected from hydrogen and (1-4C)alkyl, or an R 8  and an R 9  group attached to the same carbon atom form a cyclopropyl ring; 
 Z is selected from hydrogen, OR 11  and NR 12 R 13 ; 
 R 11 , R 12  and R 13  are each, independently, selected from hydrogen and (1-4C)alkyl; and 
 R 10  is selected from (1-4C)alkoxy and NR 12 R 13 , wherein R 12  and R 13  are as defined above, 
 wherein any CH 2  or CH 3  group within a Z or an R 10  group optionally bears on each said CH 2  or CH 3  group one or more substituents independently selected from halogeno, (1-4C)alkyl, hydroxy and (1-4C)alkoxy; 
 
     or a pharmaceutically acceptable salt thereof. 
   
   
       2 . The quinazoline derivative of Formula I according to  claim 1 , wherein R 1  is selected from hydrogen, hydroxy, methoxy, ethoxy and methoxyethoxy. 
   
   
       3 . The quinazoline derivative of Formula I according to  claim 2 , wherein R 1  is hydrogen. 
   
   
       4 . The quinazoline derivative of Formula I according to  claim 1 , wherein G 1 , G 2 , G 3  and G 4  are each, independently, selected from hydrogen, chloro and fluoro. 
   
   
       5 . The quinazoline derivative of Formula I according to  claim 4 , wherein G 1 , G 2 , G 3  and G 4  are all hydrogen. 
   
   
       6 . The quinazoline derivative of Formula I according to  claim 1 , wherein X 1  is C(R 7 ) 2 , wherein each R 7  is, independently, selected from hydrogen and (1-4C)alkyl. 
   
   
       7 . The quinazoline derivative of Formula I according to  claim 6 , wherein X 1  is CH 2 . 
   
   
       8 . The quinazoline derivative of Formula I according to  claim 1 , wherein Q 1  is selected from phenyl and a 5- or 6-membered monocyclic heteroaryl ring, which ring contains 1, 2 or 3 heteroatoms independently selected from oxygen, nitrogen and sulfur, which phenyl or heteroaryl group optionally bears 1, 2 or 3 substituents independently selected from halogeno, cyano and (1-4C)alkoxy. 
   
   
       9 . The quinazoline derivative of Formula I according to  claim 8 , wherein Q 1  is selected from phenyl, 2-pyridyl and 1,3-thiazol-4-yl, which optionally bears 1, 2 or 3 substituents independently selected from halogeno, cyano and (1-4C)alkoxy. 
   
   
       10 . The quinazoline derivative of Formula I according to  claim 1 , wherein R 2 , R 3 , R 4  and R 5  are each, independently, selected from hydrogen and (1-2C)alkyl. 
   
   
       11 . The quinazoline derivative of Formula I according to  claim 10 , wherein R 2 , R 3 , R 4  and R 5  are each, independently, selected from hydrogen and (1-2C)alkyl, wherein at least one of R 2 , R 3 , R 4  and R 5  is (1-2C)alkyl. 
   
   
       12 . The quinazoline derivative of Formula I according to  claim 10 , wherein R 2 , R 3 , R 4  and R 5  are all hydrogen. 
   
   
       13 . The quinazoline derivative of Formula I according to  claim 1 , wherein R 6  is methyl. 
   
   
       14 . The quinazoline derivative of Formula I according to  claim 1 , 
     wherein
 A is Z-(CR 8 R 9 ) p —; 
 p is 1 or 2; 
 R 8  and R 9  are each, independently, selected from hydrogen and (1-4C)alkyl; 
 Z is selected from hydrogen, OR 11  and NR 12 R 13 ; and 
 R 11 , R 12  and R 13  are each, independently, selected from hydrogen and (1-4C)alkyl; 
 wherein any CH 2  or CH 3  group within a Z group optionally bears on each said CH 2  or CH 3  group one or more substituents independently selected from halogeno, (1-2C)alkyl and hydroxy. 
 
   
   
       15 . The quinazoline derivative of Formula I according to  claim 14 , 
     wherein
 A is Z-(CR 8 R 9 ) p —; 
 p is 1 or 2; 
 R 8  and R 9  are each, independently, selected from hydrogen and (1-2C)alkyl; and 
 Z is hydroxy. 
 
   
   
       16 . The quinazoline derivative of Formula I according to  claim 15 , wherein A is hydroxymethyl. 
   
   
       17 . The quinazoline derivative of Formula I according to  claim 1  selected from one or more of the following: 
     2-hydroxy-N-methyl-N-{2-[(4-{[1-(pyridin-2-ylmethyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]ethyl}acetamide; 
     2-hydroxy-N-methyl-N-{2-[(4-{[1-(1,3-thiazol-4-ylmethyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]ethyl}acetamide; 
     N-{2-[(4-{[1-(3-fluorobenzyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]ethyl}-2-hydroxy-N-methylacetamide; 
     2-hydroxy-N-methyl-N-{(2R)-2-[(4-{[1-(pyridin-2-ylmethyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]propyl}acetamide; and 
     2-hydroxy-N-methyl-N-{(R)-1-methyl-2-[4-(1-pyridin-2-ylmethyl-1H-indazol-5-ylamino) quinazolin-5-yloxy]ethyl}acetamide; 
     or a pharmaceutically acceptable salt thereof. 
   
   
       18 . A pharmaceutical composition comprising a quinazoline derivative of Formula I, or a pharmaceutically-acceptable salt thereof, according to  claim 1  in association with a pharmaceutically-acceptable diluent or carrier. 
   
   
       19 . The pharmaceutical composition according to  claim 18 , further comprising an additional anti-tumour agent. 
   
   
       20 - 21 . (canceled) 
   
   
       22 . A method for producing an anti-proliferative effect in a warm-blooded animal in need of such treatment, comprising administering to said animal an effective amount of a quinazoline derivative of Formula I, or a pharmaceutically-acceptable salt thereof, according to  claim 1 . 
   
   
       23 . (canceled) 
   
   
       24 . A method for treating a disease or medical condition mediated alone or in part by erbB receptor tyrosine kinase in a warm-blooded animal in need of such treatment, comprising administering to said animal an effective amount of a quinazoline derivative of Formula I, or a pharmaceutically-acceptable salt thereof, according to  claim 1 . 
   
   
       25 . (canceled) 
   
   
       26 . A method for preventing or treating tumours which are sensitive to inhibition of one or more erbB receptor tyrosine kinase involved in signal transduction steps which lead to proliferation and/or survival of tumour cells in a warm-blooded animal in need of such treatment, comprising administering to said animal an effective amount of a quinazoline derivative of Formula I, or a pharmaceutically-acceptable salt thereof, according to  claim 1 . 
   
   
       27 . (canceled) 
   
   
       28 . A method for treating cancer in a warm-blooded animal in need of such treatment, comprising administering to said animal an effective amount of a quinazoline derivative of Formula I, or a pharmaceutically-acceptable salt thereof, according to  claim 1 . 
   
   
       29 . A process for preparing a quinazoline derivative of Formula I, or a pharmaceutically-acceptable salt thereof, according to  claim 1  comprising:
 (a) coupling, optionally in the presence of a base, a quinazoline of Formula II:   
     
       
         
         
             
             
         
       
       wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X 1 , Q 1 , G 1 , G 2 , G 3  and G 4  have the meanings defined in  claim 1  except that any functional group is protected, with a carboxylic acid of Formula III, or a reactive derivative thereof:
   A-COOH  III 
 
       wherein A has the meanings defined in  claim 1  except that any functional group is optionally protected; or 
       (b) for the preparation of the quinazoline derivatives of Formula I wherein A is Z-(CR 8 R 9 ) p — and Z is —NR 12 R 13 , coupling a quinazoline of Formula IV: 
     
     
       
         
         
             
             
         
       
       wherein L 1  is a displaceable group and p, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 8 , R 9 , X 1 , Q 1 , G 1 , G 2 , G 3  and G 4  have the meanings defined in  claim 1  except that any functional group is optionally protected, with an amine of Formula V:
   R 12 R 13 N—H  V 
 
       wherein R 12  and R 13  have the meanings defined in  claim 1  except that any functional group is optionally protected; or 
       (c) coupling, optionally in the presence of a base, a quinazoline of Formula VI: 
     
     
       
         
         
             
             
         
       
       wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , A, G 1 , G 2 , G 3  and G 4  have the meanings defined in  claim 1  except that any functional group is optionally protected, with a compound of Formula VII:
   Q 1 -X 1 -L 2   VII 
 
       wherein L 2  is a displaceable group and Q 1  and X 1  have the meanings defined in  claim 1  except that any functional group is optionally protected; or 
       (d) coupling, optionally in the presence of a base, a quinazoline of Formula VIII: 
     
     
       
         
         
             
             
         
       
       wherein L 3  is a displaceable group and R 1 , R 2 , R 3 , R 4 , R 5 , R 6  and A have the meanings defined in  claim 1  except that any functional group is optionally protected, with a compound of Formula IX: 
     
     
       
         
         
             
             
         
       
       wherein G 1 , G 2 , G 3 , G 4 , Q 1  and X 1  have the meanings defined in  claim 1  except that any functional group is optionally protected; 
     
     and optionally:
 (i) converting a quinazoline derivative of Formula I into another quinazoline derivative of Formula I; 
 (ii) removing any protecting group that is present; and/or 
 (iii) forming a pharmaceutically acceptable salt.